Introduction

Hunter syndrome is an inherited metabolic disorder that occurs when an enzyme your body needs to break down molecules called glycosaminoglycans, or mucopolysaccharides, is either missing or malfunctioning.

Because the body can't break down these complex molecules, they build up in harmful amounts in certain cells and tissues. The buildup that occurs in Hunter syndrome eventually causes permanent, progressive damage affecting appearance, mental development, organ function and physical abilities.

Hunter syndrome appears in children as young as age 2. It's rare and nearly always occurs in males, although it may occur in females. Hunter syndrome is named after Charles Hunter, a Canadian professor of medicine who first described the disorder in 1917.

Treatment of Hunter syndrome mostly involves management of symptoms and complications. Although there's no cure for Hunter syndrome, enzyme replacement therapy and other emerging therapies may offer more help in the future.

Signs and symptoms

Hunter syndrome is one type of a group of inherited metabolic disorders called mucopolysaccharidoses (MPS), and it's referred to as MPS II. There are two subtypes of Hunter syndrome, MPS II A and MPS II B.

Type MPS II A
Early-onset Hunter syndrome (MPS II A) is the more severe of the two types and usually appears around age 2 and up to age 4. This form of the disorder may result in profound mental retardation by late childhood. Children with this form of the syndrome usually don't survive beyond their teens.

Signs and symptoms of MPS II A include:

Delay in development, which usually appears between ages 1 1/2 and 3, followed by a progressive loss of skills

Coarse facial features, including thickening of the lips, tongue and nostrils

Abnormal bone size or shape and other skeletal irregularities

Enlarged internal organs, such as the liver and spleen, resulting in a distended abdomen

Respiratory difficulties A decline including sleep apnea, a condition in which breathing intermittently stops during sleep

Cardiovascular disorders, such as progressive thickening of heart valves, hypertension and obstruction of blood vessels

Vision loss or impairment from degeneration of cells that capture light and buildup of cellular debris in the brain causing pressure on the optic nerve and eye

Skin lesions on the back and upper arms

Progressive loss of hearing

Aggressive behavior

Stunted growth

Joint stiffness

Diarrhea

Type MPS II B
Late-onset Hunter syndrome (MPS II B) is milder and causes less severe symptoms that appear much later. This form is usually diagnosed after age 10, and may not be detected until adulthood. Intellectual and social development usually is nearly normal, but the condition may affect verbal and reading skills. People with this type of Hunter syndrome can live into their 50s.

Signs and symptoms of MPS II B include:

Abnormal bone size or shape and other skeletal irregularities, but less severe than in MPS II A

Somewhat stunted growth

Poor peripheral vision

Joint stiffness

Hearing loss

Diarrhea

Sleep apnea

Causes

As with all types of MPS, Hunter syndrome is caused when a person lacks a specific enzyme his or her body needs to break down glycosaminoglycans — molecules formed from long chains of complex carbohydrates.

In unaffected people, these enzymes are found in a part of cells called the lysosomes. Lysosomes break down the complex carbohydrates into nutrients, such as proteins and simpler molecules, so your body can use them at the cellular level. These nutrients help your body build bone, cartilage, tendons, corneas, skin and connective tissue, and are also found in the fluid that lubricates your joints.

The lysosomes use enzymes to break down glycosaminoglycans, as part of the body's normal recycling and renewal process. In a person with Hunter syndrome or other form of MPS, these enzymes either are missing or don't work correctly.

These breaking-down tasks involve 11 different enzymes, and the particular enzyme that is missing or malfunctioning largely determines the type of MPS disorder, also called lysosomal storage disorders. As a result of these enzyme malfunctions, undigested glycosaminoglycans collect in the cells, blood and connective tissues, causing permanent and progressive damage. In the case of Hunter syndrome, the missing or malfunctioning enzyme is called iduronate-2-sulfatase.

Risk factors

The risk of an unborn child acquiring Hunter syndrome is determined by the genetics of the child's mother.

Hunter syndrome is an X-linked recessive disease. This means that women carry the disease and pass it on — most often to their sons — but the mothers aren't affected by the disease themselves. Hunter syndrome is the only type of MPS that can be passed on by a defective gene in the mother alone. In all other types of MPS, the child inherits the syndrome because the same defective gene has been passed on by both parents.

In an X-linked recessive disorder, the mutated gene is located on the X chromosome. In this case, the mother is a carrier, which means she has one mutated gene and one normal gene for the condition. A carrier mother has a 25 percent chance of having an unaffected son, a 25 percent chance of having an unaffected daughter, a 25 percent chance of having a carrier daughter, and a 25 percent chance of having an affected son. A man with an X-linked recessive disorder will pass his normal Y gene to his sons, and none will be affected. He will pass his mutated X gene to his daughters, and they will be carriers. These chances are the same in each pregnancy.

Girls are less at risk of inheriting this disease because they have two X chromosomes. If one of the X chromosomes is defective, their normal X chromosome can provide a functioning gene. If the X chromosome of a boy is defective, however, there isn't another normal chromosome to compensate for the problem.

If you have a child with Hunter syndrome or other MPS syndrome, talk to your doctor or a genetic counselor before planning to have more children. If you're a sister or aunt of a person with Hunter syndrome, you may also be a carrier. There are tests for genetic carriers, so it's wise to seek genetic counseling before having children

Screening and diagnosis

Confirmation of a diagnosis of Hunter syndrome requires tests performed on blood, urine or tissue samples. Your doctor will look for excess glycosaminoglycans in your child's urine or a deficiency of enzymes in your child's body fluids or cells.

Sometimes secondary health issues can lead to a diagnosis of Hunter syndrome. For example, if your child has recurrent pneumonia, a chest X-ray may show irregularly shaped vertebrae and ribs, a common sign of this syndrome. This finding could lead to further testing and an earlier diagnosis of the disease. However, because the disorder progresses slowly and its signs and symptoms overlap with a number of others, definitive diagnosis may take some time.

Prenatal testing
Prenatal testing of the fluid that surrounds the baby (amniocentesis) or taking a tissue sample from the placenta (chorionic villus sampling) can verify if your child carries a copy of the defective gene or is affected with the disorder.

Complications

A variety of complications can occur with Hunter syndrome depending on the type and severity. These may include:

Respiratory complications. All forms of MPS, including Hunter syndrome, involve respiratory complications that contribute to your child's disability and sometimes cause death as the disease progresses. An enlarged tongue, thickened gums and thickening of the nasal passages and windpipe (trachea) make breathing difficult. Children often have chronic ear and sinus infections, respiratory infections and pneumonia. Sleep apnea, a condition in which breathing is intermittently interrupted during sleep, is often present because of airway constriction.

Cardiac complications. Thickening of tissue associated with Hunter syndrome can cause progressive thickening of the heart's valves. This causes improper closing of heart valves. As a result, the heart and other parts of the body don't receive blood efficiently. As the disease progresses, these conditions often become worse and typically result in heart failure.

The thickening of tissue also can cause narrowing of the aorta (coarctation) and other blood vessels. This in turn can result in high blood pressure (hypertension) and the narrowing of arteries in the lungs (pulmonary hypertension).

Skeletal and connective tissue complications. The storage of undigested glycosaminoglycans in connective tissues results in abnormalities in bone, joints and ligaments. This impairs your child's growth, causing pain and anatomical malformations, and making it difficult for him or her to move.

Nearly everyone with Hunter syndrome experiences joint stiffness, which makes movement painful. The stiffness is caused by the swelling of joint connective tissues and the abnormalities of cartilage and bones. If your child is in pain, he or she will likely move less, which can lead to more stiffness and pain.

The group of abnormalities typically seen in the bones of people with Hunter syndrome is called dysostosis multiplex. Children with these abnormalities can develop irregularly shaped vertebrae and spines (kyphoscoliosis), ribs, arms, fingers, legs and pelvises. Their skulls may press down on or fuse with their upper spines. These complications cause many people with Hunter syndrome to be abnormally short. Those with milder cases may reach normal or near-normal height.

Hernias (inguinal and umbilical) are common in Hunter syndrome. They happen because of problems with connective tissue. A hernia occurs when soft tissue, usually part of the intestine, pokes through a weak spot or tear in the lower abdominal wall. Hernias associated with Hunter syndrome can become quite large and are often one of the first signs of the disorder. Enlargement of the liver and spleen (hepatosplenomegaly), common in Hunter syndrome, may contribute to increased pressure in the abdomen and lead to hernia formation.

Brain and nervous system complications. A variety of neurological complications may be present and continue to develop in children with Hunter syndrome. Often these symptoms appear gradually, so be alert to even small changes in your child's condition. Many neurological problems are caused by buildup of excess fluids in your child's brain (hydrocephalus). Pressure from these fluids can cause spinal cord problems and may affect your child's eyes and other sensory organs, cause severe headaches, interfere with vision, and alter your child's mental state. Imaging tests may also reveal a variety of cyst-like structures in parts of the brain.

Your child may also develop a condition in which the membranes that surround the spinal cord may become thick and scarred (pachymeningitis cervicalis). This causes pressure and compression of the upper spinal cord. As a result, your child may develop fatigue in his or her legs and gradually weaken and become less physically active.

Other disorders, such as carpal tunnel syndrome, can result from nerve compression that happens because of bone deformities and storage of glucosaminoglycans in tissues.

Abnormal behavior can develop in children with a more severe case of Hunter syndrome. Often your child's mental development will begin being affected between the ages of 2 and 6. Some children become hyperactive and aggressive. Your child may have a shortened attention span, difficulty following instructions, and no sense of danger. As your child's overall physical functioning declines, these behavior problems will become less severe.

Seizures may also occur in children with Hunter syndrome.

Longer recovery from other illnesses
Be aware that recovery times from normal childhood illnesses may be longer for children with Hunter and other MPS syndromes. Therefore, be sure to take general preventive measures — for example, get your child a flu shot and ensure your child receives all necessary vaccinations.

Treatment

Because there's no cure for Hunter syndrome, treatment focuses on managing signs, symptoms and complications to provide some relief for your child as the disease progresses. Treatment may involve the following:

Relief for respiratory complications. Removal of tonsils and adenoids can open up your child's airway and relieve sleep apnea. But as the disease progresses, tissues continue to thicken and these problems can come back. Some types of breathing devices can help with upper airway obstructions and sleep apnea. Keeping your child's airway open can also avoid low blood oxygen levels (hypoxemia).

Addressing cardiac complications. Because heart disease and its complications usually are unexpected in young children, your child's doctor will want to watch closely for cardiovascular complications, such as high blood pressure, heart murmur and leaky heart valves. If your child has severe cardiovascular problems, your doctor may recommend surgery to replace heart valves.

Treatment for skeletal and connective tissue problems. Most children with Hunter syndrome don't heal well and often have complications from surgery. That limits options for addressing skeletal and connective tissue complications. For example, surgery to stabilize the spine using internal hardware is difficult when bones are fragile.

Your child's joint flexibility can be improved with physical therapy, which helps address stiffness and maintain function. However, physical therapy can't prevent the progressive decline of mobility. Your child may eventually need to use a wheelchair because of pain and limited stamina.

Surgery can repair hernias, but because of weakness in connective tissues, results usually aren't ideal. The procedure often needs to be repeated. One option is to manage your child's hernias with supportive trusses rather than surgery because of the risks of anesthesia and surgery.

Managing neurological complications. Problems associated with the buildup of fluid and tissue around the brain and spinal cord are difficult to address because of the inherent risks in treating these parts of the body. Your child's doctor may recommend surgery to drain excess fluids or remove built-up tissue.

If your child has seizures, your doctor may prescribe anticonvulsant medications.

Managing behavioral problems. If your child develops abnormal behavior as a result of Hunter syndrome, providing a safe home environment is one of the most important ways you can manage this challenge. Treating behavior problems with medications has had limited success because most medications have negative effects on other manifestations of the disease.

Addressing sleep issues. The sleep patterns of a child with Hunter syndrome become more and more disorganized, causing some children to be active around the clock. Medications including sedatives and especially melatonin can improve sleep. Keeping a strict bedtime schedule and making sure your child sleeps in a well-darkened room also can help. Sometimes it may be necessary to provide your child with a padded bedroom to prevent injury during the night.

Treatments in development
Although there's no cure for Hunter or other MPS syndromes, some treatments that are in their early stages have had some success in altering the natural course of the disease to slow its progress and lessen its severity.

These emerging treatments include:

Bone marrow transplantation. If a healthy donor is found that matches your child's blood and tissue type, bone marrow transplantation can be used to treat some symptoms in milder forms of Hunter syndrome. Bone marrow is taken from the hip of the donor and transplanted to your child by injecting it into his or her veins (intravenously). This treatment can help ease the problems of breathing; mobility; and heart, liver and spleen function. It can also help prevent your child's mental regression. This treatment won't help with bone or vision problems.

Cord blood transplantation. This treatment uses umbilical cord blood from an unrelated donor that's collected at the time of the donor's birth. The cord blood is transplanted using an IV. This treatment is designed to help your child's bone marrow and enzyme activity recover. It can also reduce the effects of the disease on facial and skin features, joint mobility, hearing and enlargement of the liver and spleen.

Enzyme therapy. This treatment uses man-made or genetically engineered enzymes, which are injected directly into your child's bloodstream to replace your child's missing or defective enzymes and ease the disease symptoms. The Food and Drug Administration gave its approval in July 2006 for the first human enzyme replacement therapy treatment for Hunter syndrome. People involved in tests of the drug idursulfase (Elaprase) showed improvement in their ability to walk after a year of weekly treatments.

These therapies show promise, but they don't provide a cure. More research is needed.

Prevention

Hunter syndrome is a genetic disorder. Talk to your doctor or a genetic counselor before having children if you or any members of your family have a genetic disorder or a family history of genetic disorders. If you think you might be a carrier, genetic tests are available. If you already have a child with Hunter syndrome, seek the advice of a doctor or genetic counselor before you have more children.

Coping skills

The challenges for parents, families and caregivers of children with severe disabilities are great. A number of organizations offer support for families with children who have Hunter syndrome and other MPS syndromes.

The intense supervision that may be needed for your child can cause you and other caregivers to become physically, mentally and emotionally exhausted. It's important to get help from other family members and to find other kinds of support.

If respite care is available, take advantage of it so that you can have a break and be more effective in the long run to meet the day-to-day challenges of caring for a child with special needs.

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